Enhancing production of the anti-inflammatory cytokine IL-10 is a promising strategy for combating pathogenic inflammation. In a study published in Nature Chemical Biology, we screened for small molecules that could increase IL-10 secretion in pathogen-sensing cells from the innate immune system. In doing so, we identified cellular circuitry that limits IL-10 production during an immune response. Two kinases, CDK8 and CDK19, are a critical part of that circuitry, and could be new targets for treating inflammatory disorders.

(Summary submitted by Ramnik Xavier, MD, PhD, Chief of the Gastrointestinal Unit and Director of Center for the Study of Inflammatory Bowel Disease, and Thomas Sundberg, PhD, Senior Research Scientist in the Center for the Development of Therapeutics at the Broad Institute)

We published findings from the Harvard Aging Brain Study (Department of Neurology, Massachusetts General Hospital) investigating the link between subjective memory complaints (when a patient reports a worsening of their thinking abilities, including memory) and Alzheimer’s disease pathology in individuals who are otherwise cognitively normal. We found that increasing memory complaints were linked with greater amounts of tau in the brain, a naturally occurring protein that is associated with neuron loss in Alzheimer’s disease. We posit that memory complaints are a very early marker of disease, as they relate to tau build up before clinical tests can detect memory impairment.

(Summary submitted by Rachel Buckley, PhD, and Rebecca Amariglio, PhD, both of the Martinos Center for Biomedical Imaging)

The November 2016 U.S. presidential election demonstrated major shifts in party voting. For example, in Texas, the Democratic candidate performed better than previous Democratic presidential nominees in any election in 20 years. However, in Wisconsin, the Republican nominee won for the first time in 32 years. Much of this shifting towards Republican voting was associated with education, race and income. In this county-level analysis, we demonstrate that even after accounting for these factors, public health of communities was significantly associated with shifting towards Republican voting in 2016 relative to 2012. This association was particularly strong in states that switched Electoral College votes. Although this analysis cannot show causality, these results raise the possibility of health of communities or factors associated with health of communities influencing the result of the presidential election.

(Summary submitted by Jason Wasfy, MD, MPhil, of the Division of Cardiology)

Our lab has identified a protein called thymocyte selection-associated high mobility box protein (TOX) as the major oncogenic driver responsible for causing genomic DNA alterations and transforming normal T cells into aggressive leukemia. TOX is also required for leukemia cell growth and thus is a new, previously unexplored therapeutic target in this disease. Importantly, TOX is expressed in 95% of human T cell acute lymphoblastic leukemia, suggesting TOX is a major oncogenic driver in a vast majority of patients with this disease. Using a wide array of functional analyses, TOX was found to be involved in the impairment of Non-Homologous End Joining repair (NHEJ), a condition which is well known to cause genomic instability. Collectively, this work has uncovered important roles for TOX in regulating elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation.

(Summary submitted by David Langenau, PhD, of the Molecular Pathology Unit)

Mutations of the PTEN gene are a step in the development of many cancers. Following the discovery that cancers with a PTEN mutation tend to use the beta version of P13K (a family of enzymes involved in cellular functions) to drive abnormal cell signaling in cancer (Jia et al. Nature 2008 Aug 7;454(7205):776-9.), SAR260301 was developed as the first-in-class PI3Kβ-selective inhibitor to enter clinical trials. As with all phase I trials, our initial goal was to establish the pharmacokinetic behavior and safety of this agent. But we also recruited patients with cancer types likely to harbor PTEN mutations. Unfortunately, we found that the pharmacokinetic properties of this agent were suboptimal, and it was unable to inhibit the intended target. We also saw very little evidence of antitumor efficacy, even in patients who were proven to have complete loss of PTEN in their tumors.

Renin-angiotensin system (RAS) inhibitors (ACE inhibitors and angiotensin receptor blockers)—widely prescribed to control blood pressure and cardiovascular diseases—may also benefit cancer patients. By targeting different cell types in the tumor milieu, as well as cancer cells directly, RAS signaling can help tumor cells to escape the immune system. RAS inhibitors may reverse these effects and promote an anti-tumor immune response. Thus, these drugs have the potential to improve the outcome of conventional cancer therapy, especially if combined with immunotherapy. Indeed, several retrospective and small prospective pilot studies, including our study, reported that the use of RAS inhibitors was associated with better outcomes in patients with different tumor types. Large prospective randomized trials are needed to confirm these promising data.

Pediatric medulloblastoma is the most common malignant brain tumor in children. Despite progress in the treatment of these tumors, toxicities associated with current treatments remain a formidable challenge. Development of novel non-toxic therapies requires animal models that recapitulate the human disease and the ability to image molecular and cellular mechanisms associated with tumor initiation, growth and therapeutic response. To this end, we developed a window that provides optical access to the mouse cerebellum and enables visualization of molecular, cellular, anatomical and functional parameters in a live animal. This new method has provided powerful insights into the inner workings of pediatric medulloblastoma as well as other malignancies of the cerebellum.

Gliomas are a common type of brain tumor. Despite treatment with aggressive therapies, including radiation and chemotherapy, gliomas are incurable and ultimately cause untimely death. This review article focuses on a subset of gliomas that carry a mutation in Isocitrate dehydrogenase 1 (IDH1). This gene encodes a critical intracellular enzyme involved in metabolism, aiding in the generation of stored energy from carbohydrates, fats and proteins. Strikingly, patients with gliomas exhibiting this mutation tend to be younger, live longer and respond better to chemotherapy than those without the mutation. IDH1 mutations disrupt normal metabolism and many studies are ongoing to take advantage of this tumor-specific change. This work highlights treatment strategies under investigation in clinical trials, including drugs that directly inhibit IDH1 mutant function, PARP inhibitors, and immunotherapy approaches.

(Summary submitted by Julie Miller, MD, of the Pappas Center for Neuro-Oncology, Department of Neurology)

Alzheimer’s disease (AD) is the most common form of dementia. Imaging of amyloid deposits using positron emission tomography (PET) is a valuable tool in AD diagnostics and research. This study features the application of a correction technique that enhances the resolution of amyloid PET images. By applying methods from graph theory, we can analyze the amyloid PET images by computing “networks” that reveal the spatial distribution patterns and spreading pathways of amyloid in different stages of AD. Our results indicate that the applied correction substantially improves our ability to distinguish between different stages of AD progression based on amyloid network structure analysis.

(Summary submitted by Quanzheng Li, PhD, of the Department of Neurology)

The risk of psychological harm may be a barrier to following national cancer screening guidelines. The authors conducted a systematic review to examine how the experience of psychological distress relates to cancer screening. The review included 22 studies that administered measures of psychological distress between 2 weeks and 1 month after the screening procedure. The review found that distress was low across screening procedures, with the exception of colorectal screening. Importantly, none of the studies in this review were conducted exclusively with the intention of assessing distress at the time of cancer screening. Findings from this review suggest that psychological distress may not be a widespread barrier to screening among adults who undergo cancer screening. However, more studies are needed using validated measures of psychological distress to better understand the extent to which screening may cause psychological distress and reduce cancer screening adherence.

(Summary submitted by Elyse Park, PhD, of the Department of Psychiatry and Emma Chad-Friedman, of the Benson-Henry Institute for Mind Body Medicine)

Although one in eight men will be diagnosed with prostate cancer in their lifetime, effective treatment of this disease is challenging. In a new study, we showed how sensitive imaging and new insights on disease mechanisms could provide better treatment of prostate cancer. Our team developed microscopic iron crystals (nanoparticles) that carried a molecular zip code to detect the presence of a prostate cancer marker in the body using magnetic resonance imaging (MRI) and positron emission tomography (PET). We also used these nanoparticles to deliver drugs to specifically kill the cancer cells, avoiding side effects of current treatments.

(Summary submitted by Charalambos Kaittanis, PhD, of the Department of Radiology)

The National Recovery Study is the first-ever nationally representative sample of individuals in recovery. Findings from the study reveal the most accurate estimate to date, that 22.35 million (9.1%) American adults have resolved an alcohol or other drug problem. Surprisingly, 51% of these problems were primarily due to alcohol, while opioids were only the primary substance in 5% of individuals. Furthermore, approximately half of all Americans who have resolved their substance problem, did so without any assistance such as treatment, detox, 12-step meetings (e.g. Alcoholics Anonymouos), medications, faith-based groups, etc, and only 46% of individuals actually go on to label themselves and identify as individuals “in recovery.”

(Summary submitted by Alexandra Plante, MA, of the Recovery Research Institute)

We have created a promising new light-activated, cancer-targeting therapeutic. Cancer drugs often cannot reach every cell in a tumor, leaving behind cells that can become resistant to treatment. At the same time, these drugs can cause unwanted systemic problems, such as weight and hair loss, elsewhere in the patient’s body. Our therapeutic was built to diffuse throughout tumors, target cancer cells, and kill these cells only when activated by light to avoid unwanted and burdensome side effects. We hope that this approach could one day find use in the fight against treatment-resistant cancers, like breast and lung.

(Summary submitted by Conor L. Evans, PhD, of the Wellman Center for Photomedicine)

Notch signaling is a cellular messaging system that is fundamental to normal tissue development. For years, researchers have known about mutations that amplify Notch signaling in cancers of mature B cells, such as mantle cell lymphoma and chronic lymphocytic leukemia, but it has been unclear why increased Notch signaling promotes these cancers. Now we have uncovered a network of genes that are specifically activated by Notch signaling in B cells, including the master cell growth regulator MYC. Other Notch-activated genes include components of B cell signaling pathways that can be blocked with clinically approved drugs, suggesting new strategies that might be tested in the future for the treatment of leukemia and lymphoma patients.

(Summary submitted by Bradley Bernstein, MD, and Russell Ryan, MD, both of the Department of Pathology)

This study compared the gene transcription profiles of CD8 T cells targeting hepatitis C virus (HCV) during the initial 18 weeks of infection in patients who did or did not successfully control the virus. The findings indicate that T cells activate differential molecular programs already very early, before there are actual differences in the control of the virus. Most notable were altered programs regulating cellular metabolism, indicating that early differences in how T cell generate the energy needed for proliferation and differentiation might dictate the ultimate fate of a nascent T cell response. As this study was performed in a diverse human population, it also identified links between these cellular programs and sex and age of the patient, two important but understudied factors for the immune response in humans.

Treatment schedules combining radiotherapy and chemotherapy play an important role in the treatment of lung cancer. There are currently few mathematical models to simulate the effect of these treatments and their interaction. In this study, we developed a mathematical formalism using clinical data from multiple clinical trials. The established model can simulate tumor growth over extended periods of time and predict survival curves for populations of non-small cell lung cancer patients receiving different treatments. This can be used not only to design personalized treatment schedules, but also play a role in the optimization of future clinical trials combining different treatment modalities.

(Summary submitted by Clemens Grassberger, PhD, of the Department of Radiation Oncology)

About one in 2,000 seemingly healthy individuals are missing a gene called CLYBL, and the only indication of this missing gene to date is low vitamin B12 levels. CLYBL encodes a metabolic enzyme, but its function was previously unknown. We have identified that CLYBL is a detoxifying enzyme, and it prevents a toxic metabolite called itaconyl-CoA from inactivating B12. Unexpectedly, the same toxin is generated from another metabolite called itaconate that is ordinarily produced by our immune system to fight infection. This work uncovers a potential connection between vitamin B12 and immune system activation.

(Summary submitted by Vamsi Mootha, MD, and Hongying (Hoy) Shen, PhD, both of the Howard Hughes Medical Institute and Department of Molecular Biology)

The ability of organs to regenerate following injury declines with age. In aged individuals, chronic tissue injury leads to abnormal wound healing responses characterized by the development of scar tissue, or fibrosis, and subsequent organ failure. The identification of novel therapeutic strategies aiming at reducing tissue fibrosis and promoting the regeneration of damaged tissues is a major unmet clinical need in regenerative medicine. Our study uncovers a new molecular mechanism of tissue fibrogenesis and demonstrates that targeting the ADAM10-sEphrin-B2 pathway in scar-forming myofibroblasts prevents lung fibrosis and restores organ function. Our findings reveal novel therapeutic targets for the treatment of a variety of human fibrotic diseases such as idiopathic pulmonary fibrosis and liver cirrhosis.

(Summary submitted by David Lagares, PhD, of the Department of Medicine)

Our study describes a previously unrecognized function of a signaling protein termed XLαs. We show that XLαs, in addition to mediating the actions of certain hormones, acts as an inhibitor of clathrin-mediated endocytosis, a fundamental process that is essential for the uptake of nutrients into cells and tissues. This action of XLαs is independent of its signaling function and appears to be critical for maintaining normal levels of iron in various tissues including heart and skeletal muscle. This study thus provides novel insights into the regulation of iron metabolism and the mechanisms regulating endocytosis.

Antibodies are proteins generated by the immune system during an initial infection or in response to a vaccine to protect us from further infections. While the front end of the antibody is responsible for the specifically recognizing a microbe, the back end coordinates a diverse set of functions locked within our immune cells to clear bacteria, viruses, fungi and parasites. What is becoming more apparent recently is that these instructions to the immune system are finely tunable by differential modifications of the antibody. We reviewed the field of antibody effector functions to explore exciting new potential paths towards improving diagnostics, guiding rational vaccine design, and developing novel therapeutics.

(Summary submitted by Lenette Lu, MD, PhD, of the Ragon Institute of MGH, MIT and Harvard)

The intestinal epithelium is a single layer of cells that protects the gut from environmental insult. Defects in this layer are linked to many diseases, including inflammatory bowel disease. Despite its critical importance, very little is known about the genes in the epithelium involved in this function. We found that transcription factor TFEB, a master regulator of lysosomal gene expression, provides a protective effect, and this function is mediated by expression of apolipoprotein A1, the major constituent of HDL, aka “good” cholesterol. Our findings suggest that enhancement of TFEB activity in the intestinal epithelium could be a therapeutic approach to enhance Apolipoprotein A1 expression for the treatment of inflammatory bowel disease.

(Summary submitted by Javier Elbio Irazoqui, PhD, formerly of the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease)

Third Harmonic Generation (THG) microscopy is a multiphoton imaging technique wherein three photons arrive simultaneously at the laser focus, producing one scattered photon at exactly three times the energy. We discovered that the three-dimensional osteocyte lacunar-canalicular network (LCN) can be clearly visualized in vivo by THG microscopy, without the need to stain or section the bone. This new imaging modality will be useful for studying the biology of osteocytes, the most abundant cell type in the bone, and for assessing the changes in LCN during aging and in various disease processes such as osteoporosis.

(Summary submitted by Charles Lin, PhD, of the Center for Systems Biology and Wellman Center for Photomedicine, and Marc Wein, MD, PhD, of the Endocrine Unit)

The MELD (model for end-stage liver disease) score is one of the widely used risk prediction scores. Especially since 2002, MELD has played a crucial role in determining which patient on the waiting list will be next to get a liver transplant. Combining the ability to store and rapidly process health records of hundreds of thousands of individuals, we took an unbiased machine learning approach toward discovery of biomarkers. We realized that by combining the components of MELD with several easily accessible variables, we could construct a new score that was significantly more accurate. We validated our approach on an independent database of more than 18 million patients and it proved superior. Our new score, denoted as “MELD-Plus,” may lead to improved care for individuals with liver disease.

(Summary submitted by Uri Kartoun PhD, of the Center for Systems Biology and Center for Assessment Technology & Continuous Health)

Cancer therapy has been transformed in the last few years by immune-based therapies, called 'checkpoint blockade' therapies. An important question is why some people respond and others do not respond to this therapy. By analyzing the DNA of tumors from patients who developed resistance to checkpoint therapy, we found changes in the DNA of a key gene that is critical for tumors to be detected by the immune system. In this way, the tumor has learned how to hide from the immunotherapy. Knowing this will help us decide which patients would benefit from immune therapy. Finding ways to make these resistant tumors visible to the immune system is an important goal for the coming years.

Medical doctors use blood counts to help diagnose and monitor almost all diseases. In the process of counting blood cells, most hematology analyzers actually measure features of thousands of individual blood cells, but this single-cell information is rarely utilized, and only the derived total cell counts are used to guide clinical care. This single-cell information helps further characterize each patient’s inflammatory or immunologic state. Using a mathematical model, we show how this routinely available single-cell information can help distinguish healthy and sick patients in general and those with acute coronary syndrome in particular. More broadly, our study shows how mathematical modeling of existing routine clinical laboratory data can help realize the vision of precision medicine today.

(Summary submitted by John Higgins, MD, of the Center for Systems Biology)

A team led by Massachusetts General Hospital investigators has identified a new cancer-causing pathway behind most cases of an aggressive type of leukemia, findings that could lead to new targeted treatment approaches.

In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD)—a neurodegenerative disease that typically claims young boys' lives within 10 years of diagnosis—effectively stabilized the disease's progression in 88 percent of patients.

A Mass General/Shriners team has developed a novel approach to drug target discovery for obesity and diabetes. The experimental and computational workflow involves the first use of rodent gastric bypass models, state-of-the-art mass spectrometry and an array of bioinformatics tools to begin unraveling how gastric bypass surgery leads to weight loss and a resolution of type 2 diabetes.

A study by Massachusetts General Hospital investigators found that surgical patients believed to be allergic to penicillin were significantly more likely to develop surgical site infections than were patients with no documented allergy, a difference totally attributable to the alternative antibiotics used to prevent such infections.

Using human induced pluripotent stem cells (iPSCs), researchers have bioengineered functional small intestine segments that, when implanted into rats, were capable of delivering nutrients into the bloodstream.

Investigators have identified differences in gene transcription within key immune cells that may distinguish those individuals infected with the hepatitis C virus (HCV) who develop chronic infection from those whose immune systems successfully clear the virus.

Researchers at Massachusetts General Hospital’s Ammon-Pinizzotto Center for Women’s Mental Health have developed the MGH Perinatal Depression Scale (MGHPDS), a free iPhone application designed to refine how women around the world are screened for postpartum depression.

A study of 100 people with acute myeloid leukemia (AML) receiving chemotherapy found that patient and physician perceptions of treatment risk and the likelihood of a cure varied widely. Overall, patients tended to overestimate both the risk of dying due to treatment and the likelihood of a cure.

A Massachusetts General Hospital study finds that hospitalized patients with advanced cancer who report more intense and numerous physical and psychological symptoms appear to be at risk for longer hospital stays and unplanned hospital readmissions.

A systematic review of published studies on the use of medical cannabis in children and adolescents finds a notable lack of studies and a minimal number of the randomized, controlled trials needed to confirm the effectiveness of a treatment.

A Massachusetts General Hospital research team has found a surprising potential solution to a persistent clinical problem—the healing of chronic wounds. In their report published in Wound Repair and Regeneration, the investigators from the MGH Vaccine and Immunotherapy Center (VIC) describe how application of mature B lymphocytes—the immune cells best known for producing antibodies—greatly accelerated the healing of acute and chronic wounds in both diabetic and nondiabetic mice. The treatment also improved the quality of regenerated tissue and reduced scarring.

Blog Posts

Massachusetts General Hospital investigators have found that the 2010 Massachusetts law restricting the use of off-road vehicles to those age 14 and older led to significant reductions in both emergency department visits and hospital admissions resulting from ORV injuries in the following three years.

A recent Pew Research Survey of 4,000 adults aged 18 and over found that only 17 percent of respondents were “active consumers” of science news. In an era where hot button issues such as childhood vaccinations have scientists facing an increasing level of scrutiny, it’s important for news sources like the Research Institute to continuously work on improving our communication skills in order to be trusted and accessible voices for science.

Researchers at Mass General-affiliated Mass Eye and Ear have discovered a way to identify patients with age-related macular degeneration (AMD), which is the leading cause of blindness in people over 50 in developed nations. Learn more about the results that might lead to earlier diagnoses and how you can slow progression of the disease known as the ‘Alzheimer's of the Eye.'

Researchers at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital are using brain imaging technology to gain new insights into how the brain systems that typically manage personal space and eye contact work differently in individuals with schizophrenia and autism.

Four Mass General researchers recently received NIH Director's New Innovator and Early Independence Awards. These awards are given to exceptionally creative scientists who propose innovative approaches with high-impact potential to major challenges in biomedical research.

On October 11th, the Mass General Research Institute hosted The Art of Talking Science: Rise of the Machines at the Russell Museum at Massachusetts General Hospital. Here’s a look back at some of the highlights from the afternoon.

A new diagnostic blood test known as a liquid biopsy has shown early promise in filling the need for a safe, fast, less expensive and accurate method for identifying early signs of cancer treatment resistance. The test also may provide new insights into the genetic changes that occur within tumor cells to drive this resistance.

Researchers from Mass General and MIT have harnessed the power of artificial intelligence (AI) to develop a wireless, portable system for monitoring sleep. The device could provide new insights into sleep disorders and reduce the need for time and cost-intensive overnight sleep studies in a clinical sleep lab.

Scientists and clinicians at Massachusetts General Hospital’s Institute for Neurodegenerative Disease (MIND) have developed an innovative approach that could significantly improve the Alzheimer's disease drug development process.